Melanocortin receptors belong to the rhodopsin sub-family of G-protein coupled receptors (GPCR's). Five different subtypes are known. These melanocortin receptors bind and are activated by peptides such as α-, β, or γ-melanocyte stimulating hormones (α-, β-, γ-MSH) derived from the pro-opiomelanocortin (POMC) gene. A wide range of physiological functions are believed to be mediated by melanocortin peptides and their receptors.    Desarnaud et al. (1994, Biochem J. 299 (2): 367-372) disclose a cDNA clone encoding mouse MC-3R.    Roselli-Rehfuss et al. (1993, Proc. Natl. Acad. Sci. 90: 8856-8860) disclose a cDNA clone encoding rat MC-3R cDNA.
U.S. Pat. No. 5,622,860 (issued Apr. 22, 1997) and U.S. Pat. No. 5,703,220 (issued Dec. 30, 1997) to Yamada and Gantz, disclose DNA molecules which encode human MC-3R and human MC-4R, respectively (see also Gantz, et al., 1993, J. Biol. Chem. 268(11): 8246-8250).
The agouti mouse represents a naturally occurring obese rodent, with a late life onset of obesity which is not corticosterone dependent. The obesity in this model results from the ectopic expression of the 131 amino acid agouti protein. Agouti is normally only expressed in the skin where it controls hair color. The protein is a paracrine antagonist of the melanocortin-1 receptor (MC-1R), a G-protein coupled receptor of the hair follicle. MC-1R agonism, through its natural ligand, α-MSH raises cAMP and the expression of the enzyme tyrosinase. Low levels of tyrosinase, which result from agouti antagonism of MC-1R, result in reduced conversion of the hair color pigment pheomelanin to eumelanin. As a result a light (agouti) rather than black hair color results. The obese phenotype of the agouti mouse was ascribed to the expression of agouti in the brain, where it antagonizes MC-3R and MC-4R receptors. This conclusion was corroborated by the generation of an MC-4R knockout mouse which recapitulates the obese phenotype of the agouti mutant mouse (see U.S. Pat. No. 5,932,779, issued Aug. 3, 1999 to Lee et al.) In rodents, MC-4R has been implicated as a key regulator of feeding behavior which regulates body weight through studies with peptide agonists and antagonists (Fan et al., 1997, Nature 385: 165-168) and with a MC-4R knock-out mouse (Huszar et al., 1997, Cell 88: 131-141, see also U.S. Pat. No. 5,932,779, issued Aug. 3, 1999 to Lee et al).
It is desirable to discover new drugs for the treatment of body weight disorders which selectively modulate a melanocortin receptor within the host.
It is also desirable to identify additional receptor targets which are involved in regulating body weight.
The present invention also addresses and meets these needs by disclosing MC-3R-deficient animal cells and/or MC-3R/MC-4R deficient animal cells, related non-human transgenic embryos, non-human transgenic animals and non-human transgenic littermates which are also MC-3R-deficient or MC-3R/MC-4R deficient.
The present invention addresses and meets these needs by disclosing methods of screening for compounds which effect body weight comprising the screening and selection of compounds which modulate the MC-3R.